The principle objective of this project is to define and characterize the consequences of HIV-1 envelope mediated signals on CD4+ T-cells and macrophages. We are specifically interested in how envelope-receptor interactions influence viral replication and HIV associated immune system dysfunction. HIV envelope proteins induce a number of biological responses in primary T-cells and macrophages ranging from the induction of pro-inflammatory cytokines to increased rates of apoptosis. Of note, many of these responses correlate with the immune dysfunction associated with HIV disease. We have demonstrated that HIV envelope induces signals through CCR5, an important co-receptor for the binding of HIV to CD4+ T cells and macrophages. In addition, we have demonstrated that gp120, the envelope spike of HIV, induces the activation of Caspase-3 and Caspase-6. These two enzymes play a critical role in the induction of apoptosis. In this regard we have provided important information relevant to the origin of HIV induced immune dysfunction. One of our principle objectives is to globally define the response of both CD4+ lymphocytes as well as macrophages to envelope mediated signaling. Important changes in cell function are frequently associated with changes in gene expression. In this regard we have employed high density oligonucleotide microarrays to identify changes in transcriptional patterns of total PBMCs and macrophages. The microarrays we are employing encompass more than 10,000 genes, including all sequences currently catalogued in GENBANK. Utilizing this powerful new technology we have identified a number of previously undescribed responses of the human immune system to HIV-1 envelope. We are investigating the genes identified in these analyses for their potential relevance to HIV-1 associated immune-dysfunction.